We propose to develop a large, high performance X-ray detector system for protein crystallography at synchrotron beamlines, using Active Pixel Matrix Sensor CMOS (complementary metal-oxide-semiconductor) technology. It will be a 47.05cm x 44.32cm (4700 x 4428 pixel) system of 1005m pixels. Each pixel will be inactive for just 225s during frame readout; the entire detector will be read out in 0.033s. The total electronic system noise will be less than the signal from a single 12keV X-ray photon, and also less than a single digital interval in its 16-bit precision readout. Its spatial resolution, dynamic range, sensitivity, and detective quantum efficiency will equal or exceed those of current CCD systems. The retail cost will be half that of today's commercial CCD systems, and substantially less than the Swiss PILATUS (www.dectris.com), against which our system will explicitly compete. It will be designed to operate without a timing shutter, allowing the sample crystal to rotate continuously. At synchrotron X-ray beamlines designed for protein crystallography today, the dominant detector systems are arrays of CCD sensors, coupled to a phosphor film by tapered fiberoptics (Westbrook & Naday, 1997). These systems are expensive: a 31.5cm x 31.5cm detector system today costs $845,000. While these systems are good, they could be better. Recently, a silicon pixel array detector system (SPAD) has arrived on the market: the PILATUS 6M, a spin-off from the ATLAS detector system at the LHC particle accelerator in Geneva. Over twice as expensive as a comparable CCD system, it provides interesting performance augmentations over CCDs but also exhibits design problems (it derives from high-energy physics, not molecular biology!). We argue in this proposal that a CMOS active pixel matrix system, explicitly designed for structural biology by structural biologists, offers all the advantages of a SPAD system with none of its disadvantages, and at considerable cost savings. PUBLIC HEALTH RELEVANCE: Protein crystallography is a mature and important enabling technology for the biological sciences and in pharmaceutical development, for determining the structures of large biological molecules: proteins and nucleic acids. The present proposal will enhance the efficacy of protein crystallography, by improving the X-ray detectors that record the diffraction data from protein crystals at synchrotron user facilities. The detector we wish to develop is faster, higher-resolution, higher precision, and more efficient than the detectors now used by protein crystallographers, and it will be half the price of its competitors.